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Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction.

Murdoch CE, Alom-Ruiz SP, Wang M, Zhang M, Walker S, Yu B, Brewer A, Shah AM - Basic Res. Cardiol. (2011)

Bottom Line: Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates.Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation.Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre, London, UK.

ABSTRACT
NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are known to be involved in angiotensin II-induced hypertension and endothelial dysfunction. Several Nox isoforms are expressed in the vessel wall, among which Nox2 is especially abundant in the endothelium. Endothelial Nox2 levels rise during hypertension but little is known about the cell-specific role of endothelial Nox2 in vivo. To address this question, we generated transgenic mice with endothelial-specific overexpression of Nox2 (Tg) and studied the effects on endothelial function and blood pressure. Tg had an about twofold increase in endothelial Nox2 levels which was accompanied by an increase in p22phox levels but no change in levels of other Nox isoforms or endothelial nitric oxide synthase (eNOS). Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates. Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation. Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose. These results indicate that an increase in endothelial Nox2 levels contributes to angiotensin II-induced endothelial dysfunction, vascular remodeling and hypertension.

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Aortic hypertrophy and ERK signaling. a Representative images of H&E-stained aortic sections from WT and Tg mice treated with infusion of saline, low dose AngII or high dose AngII. Scale bars 50 μm. b Mean data for aortic medial thickness from experiments illustrated in a. *P < 0.05 sal versus AngII, #P < 0.05 WT AngII versus Tg AngII; two-way ANOVA; n = 5 per group. c Levels of ERK1/2 phosphorylation in WT and Tg aorta after 14-day treatment with saline or high dose AngII. Representative blots are shown at the top and mean data at the bottom. p-ERK1/2, phospho-ERK1/2; pan-ERK1/2, total ERK1/2. n = 4, *P < 0.05 sal versus AngII, #P < 0.05 WT AngII versus Tg AngII
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Fig6: Aortic hypertrophy and ERK signaling. a Representative images of H&E-stained aortic sections from WT and Tg mice treated with infusion of saline, low dose AngII or high dose AngII. Scale bars 50 μm. b Mean data for aortic medial thickness from experiments illustrated in a. *P < 0.05 sal versus AngII, #P < 0.05 WT AngII versus Tg AngII; two-way ANOVA; n = 5 per group. c Levels of ERK1/2 phosphorylation in WT and Tg aorta after 14-day treatment with saline or high dose AngII. Representative blots are shown at the top and mean data at the bottom. p-ERK1/2, phospho-ERK1/2; pan-ERK1/2, total ERK1/2. n = 4, *P < 0.05 sal versus AngII, #P < 0.05 WT AngII versus Tg AngII

Mentions: To assess whether the vasculature of Tg and wild-type mice had undergone angiotensin II-induced structural remodeling, we quantified medial area in aortic sections obtained from animals subjected to angiotensin II or saline infusion. A similar increase in medial area was found in Tg and wild-type mice subjected to low dose angiotensin II infusion (0.3 mg/kg/day) (Fig. 6a). With the higher dose infusion of angiotensin II (1.1 mg/kg/day), however, aortic medial thickness was significantly greater in Tg compared to wild-type (Fig. 6a). The mean data for these experiments are shown in Fig. 6b. Finally, we investigated the effect of Nox2 overexpression on the activation of ERK1, which may be involved in angiotensin II-induced structural remodeling. The protein levels of phospho-ERK were similar in unstimulated wild-type and Tg aorta but in angiotensin II-treated aorta, the levels of phospho-ERK were significantly greater in the Tg group (Fig. 6c).Fig. 6


Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction.

Murdoch CE, Alom-Ruiz SP, Wang M, Zhang M, Walker S, Yu B, Brewer A, Shah AM - Basic Res. Cardiol. (2011)

Aortic hypertrophy and ERK signaling. a Representative images of H&E-stained aortic sections from WT and Tg mice treated with infusion of saline, low dose AngII or high dose AngII. Scale bars 50 μm. b Mean data for aortic medial thickness from experiments illustrated in a. *P < 0.05 sal versus AngII, #P < 0.05 WT AngII versus Tg AngII; two-way ANOVA; n = 5 per group. c Levels of ERK1/2 phosphorylation in WT and Tg aorta after 14-day treatment with saline or high dose AngII. Representative blots are shown at the top and mean data at the bottom. p-ERK1/2, phospho-ERK1/2; pan-ERK1/2, total ERK1/2. n = 4, *P < 0.05 sal versus AngII, #P < 0.05 WT AngII versus Tg AngII
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Related In: Results  -  Collection

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Fig6: Aortic hypertrophy and ERK signaling. a Representative images of H&E-stained aortic sections from WT and Tg mice treated with infusion of saline, low dose AngII or high dose AngII. Scale bars 50 μm. b Mean data for aortic medial thickness from experiments illustrated in a. *P < 0.05 sal versus AngII, #P < 0.05 WT AngII versus Tg AngII; two-way ANOVA; n = 5 per group. c Levels of ERK1/2 phosphorylation in WT and Tg aorta after 14-day treatment with saline or high dose AngII. Representative blots are shown at the top and mean data at the bottom. p-ERK1/2, phospho-ERK1/2; pan-ERK1/2, total ERK1/2. n = 4, *P < 0.05 sal versus AngII, #P < 0.05 WT AngII versus Tg AngII
Mentions: To assess whether the vasculature of Tg and wild-type mice had undergone angiotensin II-induced structural remodeling, we quantified medial area in aortic sections obtained from animals subjected to angiotensin II or saline infusion. A similar increase in medial area was found in Tg and wild-type mice subjected to low dose angiotensin II infusion (0.3 mg/kg/day) (Fig. 6a). With the higher dose infusion of angiotensin II (1.1 mg/kg/day), however, aortic medial thickness was significantly greater in Tg compared to wild-type (Fig. 6a). The mean data for these experiments are shown in Fig. 6b. Finally, we investigated the effect of Nox2 overexpression on the activation of ERK1, which may be involved in angiotensin II-induced structural remodeling. The protein levels of phospho-ERK were similar in unstimulated wild-type and Tg aorta but in angiotensin II-treated aorta, the levels of phospho-ERK were significantly greater in the Tg group (Fig. 6c).Fig. 6

Bottom Line: Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates.Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation.Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre, London, UK.

ABSTRACT
NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are known to be involved in angiotensin II-induced hypertension and endothelial dysfunction. Several Nox isoforms are expressed in the vessel wall, among which Nox2 is especially abundant in the endothelium. Endothelial Nox2 levels rise during hypertension but little is known about the cell-specific role of endothelial Nox2 in vivo. To address this question, we generated transgenic mice with endothelial-specific overexpression of Nox2 (Tg) and studied the effects on endothelial function and blood pressure. Tg had an about twofold increase in endothelial Nox2 levels which was accompanied by an increase in p22phox levels but no change in levels of other Nox isoforms or endothelial nitric oxide synthase (eNOS). Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates. Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation. Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose. These results indicate that an increase in endothelial Nox2 levels contributes to angiotensin II-induced endothelial dysfunction, vascular remodeling and hypertension.

Show MeSH
Related in: MedlinePlus